New methods for preventing, slowing the progression of, and treating Alzheimer's disease (AD) are urgently needed given the dramatic growth in the number of people afflicted with AD. Such efforts would be helped if AD could be detected in its preclinical stage, before irreversible brain changes occur. One approach, followed in the proposed research, is to examine individuals who are not demented but are at increased risk for developing AD due to inheritance of the epsilon4 allele of the apolipoprotein E gene (APOE) on chromosome 19. Nondemented persons with the APOE-epsilon4 genotype exhibit regional cerebral metabolic changes in association temporal, parietal, and frontal cortical areas that mirror those seen in mildly demented AD patients. These brain regions include distributed networks that mediate visuospatial attention and spatial working memory. The proposed research will therefore investigate the hypothesis that nondemented APOE-epsilon4 carriers have selective deficits in specific component processing operations underlying attention and memory. The goal is to investigate changes over time in preclinical AD in component operations of attention, working memory, and their neurobiological correlates, using information-processing tests, event-related brain potentials (ERPs), and biological markers (beta-amyloid and tau). These measures will be obtained in middle-aged nondemented adults genotyped for APOE, AD patients, and age-matched controls. A unique aspect of the research is the comprehensive approach to assessment of longitudinal changes, including behavioral, electrophysiological, and biological measures. Five studies are proposed, one large-scale study and four additional experiments. These studies will ascertain the cognitive impact of APOE in otherwise asymptomatic adults and will establish the relationship between changes in attention and working memory in preclinical and early AD. The results will have significant implications for the early detection of AD as well as for an understanding of the genetic basis of normal cognitive operations underlying attention and memory.